anti-misuse microparticulate oral pharmaceutical form

ABSTRACT

The present invention relates to solid microparticulate oral pharmaceutical forms whose composition and structure make it possible to avoid misuse of the pharmaceutical active principle (AP) they contain. 
     The object of the present invention is to prevent solid oral drugs from being misappropriated for any use other than the therapeutic use(s) officially approved by the competent public health authorities. In other words, the object is to avoid the voluntary or involuntary misuse of solid oral drugs. 
     The invention relates to a solid oral pharmaceutical form which is characterized in that it contains anti-misuse means, in that at least part of the AP it comprises is contained in coated microparticles for modified release of the AP, and in that the coated microparticles of AP have a coating layer (Ra) which assures the modified release of the AP and simultaneously imparts crushing resistance to the coated microparticles of AP so as to avoid misuse.

CLAIM FOR PRIORITY

This application is a divisional of U.S. application Ser. No.11/439,432, filed May 24, 2006, which claims priority to U.S.Provisional Patent Application Ser. No. 60/735,182, filed Nov. 10, 2005,and FR 05/53437, filed Nov. 10, 2005; the contents of which are hereinincorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to solid microparticulate oralpharmaceutical formulations whose composition and structure make itpossible to avoid misuse of the pharmaceutical or veterinary activeprinciple (AP) they contain.

The active principles (AP) in question are pharmaceutical or veterinaryAP, for example those classed in the category of stupefacient products,analgesics or narcotics. Misuse of these pharmaceutical activeprinciples can give rise to drug addiction behavior.

In terms of the present disclosure, the expression “AP” denotes both asingle active principle and a mixture of several active principles.

Microparticulate pharmaceutical formulation is understood in terms ofthe present invention as meaning any form in which the AP is containedin microparticles smaller than 1000 μm. These particles containing theAP can be coated microparticles for modified release of the AP. In thelatter case, the microparticles are coated e.g. with a polymer filmwhich controls the rate of release of the AP after oral administration.

PRESENTATION OF THE PROBLEM

The object of the present invention is to prevent solid oral drugs frombeing misappropriated for any use other than the therapeutic use(s)officially approved by the competent public health authorities. In otherwords, the object is to avoid the voluntary or involuntary misuse ofsolid oral drugs.

Misuse is mainly encountered in the following cases:

a) addictive behavior (drug addiction, doping),b) criminal behavior (chemical subjection),c) use of a drug in a manner that does not comply with the medicalrecommendations (dosage), due to carelessness or because of disabilitiesaffecting the patient.

In case a. (or even in case b.), persons intending to misuse the solidoral drug will generally endeavor to extract the AP from themodified-release form to give a quick-acting form, and then:

either convert it to a pulverulent form by crushing so that it can beinhaled or swallowed,

or convert it to a liquid form which can be injected with a syringe orswallowed.

The preparation of a liquid form from a solid oral drug involves anintermediate step for aqueous or organic extraction of the AP inquestion. This extraction is generally preceded by crushing.

The modes of administration by inhalation or injection are particularlysuited to drug addicts because these are modes which make it possible toaccentuate the effects of the AP and which favor its absorption in theorganism over short periods of time. When the powder obtained bycrushing is sniffed or dissolved in water and injected, the desireddoping or euphoriant effects of the AP manifest themselves very rapidlyand in an exacerbated manner.

At the present time there is also a particularly serious undesirablebehavior which affects teenagers and concerns analgesic AP (aAP), moreespecially morphine and opium derivatives. In fact, teenagers preparefor their parties a cocktail of vodka with oxycodone, which they easilyextract from the tablets with water and alcohol. This process consistsin crushing the tablet and pouring the powder into a glass of vodka orwater and then waiting for a sufficient time to completely extract themorphine derivatives, which can subsequently be absorbed.

Solid oral drugs can also be misused by chewing the drug beforeswallowing it, instead of swallowing it quickly in accordance with thedosage instructions.

The risks associated with addictive behavior (a.) and criminal behavior(b.) are obvious. It is pointed out that the misuse of drugs byinjection is worse: the excipients can be responsible for local tissuenecrosis, infections, and respiratory and cardiac disorders.

As regards the misuse of a drug associated with carelessness and/or thepatient's disabilities (c.), this can also have serious consequences.For example, the chewing of modified-release forms of AP beforeswallowing converts the drug to an immediate-release form. Thus at bestthe drug will become ineffective after a very short time, and at worstit will become toxic.

There is therefore clearly a serious public health problem associatedwith the misuse of drugs, particularly solid oral drugs and especiallythose based on analgesics or narcotics. This growing phenomenon is ofever greater concern to the health authorities, especially in the UnitedStates and Europe, who are increasingly appealing for the development ofpharmaceutical formulations that prevent misappropriation.

PRIOR ART

U.S. Pat. No. 6,696,088 relates to a multiparticulate oralpharmaceutical formulation that is indicated as being resistant tomisuse. It comprises particles of opioid agonist AP in amodified-release form and particles containing an opioid antagonist. Theform containing the antagonist is described as releasing less than 36%,and preferably less than 6.2%, of the antagonist AP over a period of 36h. The two types of particles are interdispersed.

When misuse is being practiced, the consequence of crushing themicroparticles to extract the opioid AP is to release the AP and itsantagonist immediately and concomitantly and thereby to limit thedesired effects of the misappropriated opioid.

As we understand it, said invention is based on the use of an activesubstance other than the AP and does not propose, inter alia, a solutionfor reducing the impact of crushing or reducing the extraction of theAP. Patent application US-A-2003/0068371 describes an oralpharmaceutical formulation comprising an opiate AP (oxycodone), anantagonist of this AP (naloxone) and a gelling agent (e.g. xanthan gum).In particular, said US patent application discloses matrix granules ofAP comprising lactose, xanthan gum, povidone and an outer coating basedon EUDRAGIT RS 30D®/triacetin/antagonist. The gelling agent is presentedas giving the formulation a viscosity such that it cannot beadministered nasally or parenterally. As we understand it, this answeris inadequate because, according to said invention, the use of anantagonist is, inter alia, obligatory. Finally, this formulationcontains no anti-crushing means, so it can be converted to a pulverulentform and consequently be the subject of misuse by the nasal or oralroute.

Patent application WO-A-03/013479 describes an oral pharmaceuticalformulation comprising an opiate analgesic and an opiate antagonist(naltrexone) in a pharmaceutically effective amount, together with abitterness promoter. When the drug addict crushes the tablet, the opioidand its antagonist are released. The opioid effect is then neutralized.As we understand it, this system does not make it possible, inter alia,to prevent selective extraction of the opioid with water, withoutcrushing.

In general, resorting to antagonists is not without its disadvantages inrespect of the possible medical risks run by the users and the risks ofinhibition of the intended therapeutic effect.

Patent application WO-A-2004/054542 describes a semiliquid oralpharmaceutical form. It takes the form of a capsule (for example gelatincapsule) comprising the AP in a matrix phase composed of awater-insoluble high-viscosity liquid (sucrose acetate isobutyrate) anda polymer (cellulose acetate butyrate) that supposedly forms a networkin the liquid phase. The formulation can optionally comprise a compoundthat modifies the rheology of the pharmaceutical form, and a solvent. Byvarying the different compounds and the concentration of theformulation, the authors state that they are able to modify the plasmaprofiles of the AP (oxycodone base) administered to dogs. As weunderstand it, this reference provides no solution for hindering, interalia, misuse by injection, all the less because the viscosity of thisformulation drops sharply with small additions of ethanol.

Patent application US-A-2003/0224051 describes an osmotic form for themodified release of oxycodone. This form consists of a tablet comprisinga core of oxycodone or one of its salts, a semipermeable membraneenveloping at least part of the core, and an outlet orifice in themembrane to allow the release of the oxycodone. This type of tabletenables the opioid to be extracted easily by immersion in water for e.g.at least 12 hours. As we understand it, this tablet is not anappropriate solution to the problem of misuse.

Patent application EP-A-1 293 209 discloses an anti-misuse solid oralpharmaceutical formulation for the prolonged release of an opioidderivative (AP) contained in an ion exchange resin. The resultingAP/resin complex makes it possible to limit the plasma concentrationobtained after misuse by chewing, inhalation or injection to atherapeutic concentration well below that sought by the misuser. TheAP/resin complex takes the form of a matrix. As we understand it, noanti-crushing means is provided in the pharmaceutical formulationaccording to said prior art document. Furthermore, this pharmaceuticalformulation contains no means for combating solvent extraction of theAP. It is therefore incapable of preventing solvent extraction of theAP, although the extraction time is longer than the normal release timeof the AP. If this oral pharmaceutical formulation is left in a glass ofwater for 24 h, virtually all the AP is extracted. Patent applicationsUS-A-2003/0118641 and 2005/0163856 (=WO-A-01/08661) describe oralpharmaceutical formulations for the prolonged release of AP consistingof opioid compounds (analgesics) and their salts. These formulationssupposedly prevent misuse by extraction of the AP with common solvents.These anti-misuse formulations do not contain antagonists, although thispossibility can be envisaged in order to be even more dissuasive. Theseformulations comprise a mixture of:

a hydrophilic matrix agent (hydroxyalkyl cellulose) in an amount of40-65% by weight;

an ion exchange resin (particles smaller than 50 μm in an amount of5-15% by weight);

and at least one opiate AP.

After the incorporation of conventional compression additives, thismixture is converted to tablets.

This is therefore a macroscopic matrix system comprising particles ofion exchange resin complexed with the AP, and an anti-extraction meansconsisting of a viscosifier, preferably hydroxypropyl methyl cellulose.As we understand it, this system is capable of improvement, especiallyin terms of anti-misuse efficacy.

Intermediate patent document WO-A-2005/079760 discloses a pharmaceuticalformulation consisting of rubbery microparticles of AP obtained byextrusion, permitting prolonged release of the AP and having anti-misuseproperties. These extruded microparticles comprise a matrix formed of aninert poly(ethyl acrylate/methyl methacrylate) copolymer: EUDRAGIT® NE30D or NE 40D. This matrix contains the AP (oxycodone), anotherEudragit®, RS PO, a plasticizer and a lubricant.

Misuse is prevented by an anti-crushing means that only involves therubbery character of the matrix particles for modified release of theAP. As we understand it, no means is provided for combating extractionof the AP in a solvent medium.

As we understand the prior art, none of the anti-misuse solutionsproposed hitherto is satisfactory, especially in terms of preventingabusive extraction of the AP with water, alcohol or other potablesolvents.

OBJECTS OF THE INVENTION

Under these circumstances, one of the objects of the present inventionis to overcome the inadequacies of the prior art.

Another object of the invention is to provide novel solid oral drugswhose misuse will be made difficult, if not impossible, especially forcases (a.)(b.)(c.) referred to above, preferably without resorting tosubstances, other than the AP, that are capable of beingpharmaceutically active and hence dangerous for the users, or even APinhibitors, for example AP antagonists.

Another object of the invention is to provide novel solid oral drugswhose misuse will be made difficult, if not impossible, especially forcases (a.)(b.)(c.) referred to above, even after a “long” liquidextraction of the AP (e.g. an analgesic). In terms of the presentdisclosure, a “long” liquid extraction is an extraction lasting morethan 10 min.

Another object of the invention is to provide novel solid oral drugsthat prevent misuse by short liquid extraction and/or crushing.

Another object of the invention is to provide novel solid oral drugshaving the following characteristics:

under normal conditions of administration, these solid oral drugs have atherapeutic effect for e.g. 12 or 24 hours;

any attempt at abusive extraction of the AP (e.g. an analgesic) willcause the drug to be converted to a form such that, after it has beeningested, rapid absorption of the AP in the blood stream will beimpossible.

Another object of the invention is to provide novel solid oral drugswhich:

can easily be administered to patients who have difficulties inswallowing large tablets, for example seriously ill patients, infants orchildren;

make it possible to associate several AP in one and the same dosageunit, even if these AP are not mutually compatible and/or do not havethe same release kinetics;

can exist in forms which can be administered one or more times a day andin which it is possible easily and independently to adjust the releaserate and time of different AP.

Another object of the invention is to provide novel solid oral drugswhose in vitro dissolution profile is independent of the dose of AP.

Another object of the invention is to provide novel solid oral drugswhich make it possible to avoid fraudulent misappropriation of theproperties of the AP they contain by preventing any conversion of thedrug to a form that can be taken orally, nasally and/or by injection(intravenously, subcutaneously, intramuscularly, etc.) outside thetherapeutic limits. This would prevent or at least greatly reduce therisks associated with this undesirable behavior.

Another object of the invention is to provide novel solid oral drugsthat make it possible to avoid misuse while at the same timeguaranteeing that the patient undergoing normal follow-up has a qualityof treatment and, in particular, a dose that conform to his needs.

Another object of the invention is to provide novel solid oral drugsthat make it possible to avoid misuse without affecting thepharmacological properties of the drug, without causing the patient whouses the drug normally to run additional risks, and finally withoutdetracting from the patient's comfort when the drug is administered.

Another object of the invention is to provide novel solid oral drugsthat can be administered one or more times a day and limit the risks ofdamage to the tissues due to local overconcentrations of AP.

Another object of the invention is to provide novel solid oral drugswhich can take a variety of galenical forms such as tablets, powdersachets, capsules and the like.

Another object of the invention is to provide novel anti-misuse solidoral drugs which are easy and economic to prepare.

BRIEF DESCRIPTION OF THE INVENTION

To achieve these objects, it is to the inventors' credit to havereformulated the general problem of the misuse of pharmaceuticalformulations.

If the different illicit modes of administration of an active principleare examined, it seems in fact that crushing of the dry form is usuallyan obligatory step.

In the case of misuse by nasal administration, the dry pharmaceuticalformulation first has to be converted to a pulverulent powder suitablefor sniffing. Crushing of the pharmaceutical formulation is thereforecertainly an obligatory step.

In the case of misuse by the oral administration of a prolonged-releasedry form, it is necessary to accelerate the release of the activeprinciple by finely crushing the microparticles or the tablet.

In the case of misuse by parenteral administration, the AP first has tobe extracted into a liquid phase, which in practice is water or organicsolvents, to a sufficiently high concentration to avoid injectingexcessively large volumes, e.g. greater than 1 ml. This extraction stepis facilitated by a previous step in which the dry form is crushed sothat the active principle can be dissolved or suspended. Moreover, afterthis extraction phase, misuse is only possible if the viscosity of theliquid is not too high (e.g. less than or equal to 100 mPa·s).

Thus the crushing of a dry form is also an obligatory step for misuse ofsaid pharmaceutical formulation by parenteral administration.

It is to the Applicant's credit to have reformulated the problem ofcombating the misuse of dry pharmaceutical formulations bycharacterizing

a primary problem (a) of preventing crushing of the system containingthe AP;

and a secondary problem (b) of preventing misuse of the AP after itspossible extraction.

This novel approach enabled the Applicant to discover, surprisingly andunexpectedly, that it is appropriate to incorporate, into thecomposition of the drug whose misuse it is sought to prevent, the AP inthe form of coated microparticles for modified release of the AP and,optionally, a combination of pharmaceutically acceptable excipients, inmicroparticulate or non-microparticulate form, whose physicochemicalmode of action makes it possible to thwart any voluntary or involuntaryact of misuse, or even render it impossible.

Thus the invention relates mainly to a solid oral pharmaceuticalformulation which is characterized in that it contains anti-misusemeans, in that at least part of the AP it comprises is contained incoated microparticles for modified release of the AP, and in that thecoated microparticles of AP have a coating layer (Ra) which assures themodified release of the AP and simultaneously imparts crushingresistance to the coated microparticles of AP so as to avoid misuse.

The pharmaceutical formulation according to the invention solves inparticular the main problem presented and meets at least some of theobjectives set, in an effective, simple and economic manner, with theaid of physicochemical means. The latter are totally inoffensive to thenormal user. They are pharmacologically inert compounds that areapproved by the pharmacopeia and by the public health authoritiesresponsible for granting drug marketing authorizations.

In one preferred embodiment, the solid oral pharmaceutical formulationaccording to the invention contains, in addition to the anti-crushingcoating layer (Ra), at least one viscosifier (Vb) that makes it verydifficult, if not impossible, to extract the AP contained in the coatedmicroparticles of AP so as to avoid misuse of the AP after liquidextraction.

In terms of the present disclosure, the expression “viscosifier” denotesboth a single viscosifier and a mixture of several viscosifiers.

DETAILED DESCRIPTION OF THE INVENTION

According to the invention, at least part of the AP is in amodified-release form, namely in the form of coated microparticles formodified release of said AP.

The active principles (AP) considered in the present invention arepharmaceutical or veterinary AP, for example those classed in thecategory of analgesics or narcotics. Misuse of these AP can give rise toaddiction behavior.

In terms of the present invention, the expression “AP” denotes oneactive principle or a mixture of several active principles.

In terms of the present invention, “microparticulate form” is understoodas meaning any pharmaceutical formulation in which the AP is containedin microparticles smaller than 1000 microns. These particles containingthe AP can be microparticles individually coated with a film formodified release of the AP. In the latter case, the microparticles arecoated e.g. with a polymer-based film which controls the rate of releaseof the AP.

In the present disclosure, “modified-release form” denotes a form inwhich at least a fraction of the AP is released at a rate slower thanthat of an immediate-release form. This fraction can be e.g. between 1and 100%, preferably between 10 and 100% and particularly preferablybetween 30 and 100%. In particular, a modified release can be prolongedand/or delayed and/or in the form of one or more release peaks (pulses).Modified-release formulations are well known in this field; cf., forexample, Remington's The science and practice of pharmacy, 19th edition,Mack Publishing Co., Pennsylvania, USA.

In the present disclosure, “immediate-release form” denotes a form whichreleases the bulk of the AP it contains over a relatively short period,i.e. at least 70% of the AP is released in 1 hour, preferably in thirtyminutes, at any pH between 1.4 and 6.8 in an in vitro dissolution test.

All the in vitro dissolution profiles referred to in the presentdisclosure are obtained as indicated in the European Pharmacopoeia 4thedition, entitled “Dissolution test for solid oral forms”: type IIdissolutest performed under SINK conditions at 37° C. and stirred at 75rpm.

The pharmaceutical formulation according to the invention is therefore aformulation for modified release of the AP.

In terms of the invention, “pharmaceutical formulation” is to beunderstood in the broad sense, i.e. this phrase also encompassesveterinary and dietetic formulations.

This pharmaceutical formulation can also comprise one or more forms forimmediate release of the AP.

Advantageously, the pharmaceutical formulation according to theinvention, which is novel in its structure, presentation andcomposition, can exist e.g. in the form of a tablet, a powder sachet, amultidose reconstitutable suspension powder sachet, or a capsule.

Coated Microparticles of AP

The coated microparticles for modified release of the AP areadvantageously microparticles that are each coated with at least onecoating (comprising e.g. at least one polymer) deposited by thetechniques known to those skilled in the art. The following work, forexample, may be consulted on this question: Formes pharmaceutiquesnouvelles: aspects technologique, biopharmaceutique et médical (Newpharmaceutical formulations: technological, biopharmaceutical andmedical aspects) by Buri, Puisieux, Doelker and Benoit, éditionsLavoisier 1985, pages 175 to 227.

In other words, these coated microparticles preferably each consist of acore comprising AP and a coating comprising at least one coating layerthat envelops the core (preferably entirely) and governs the modifiedrelease (preferably continuous) of the AP. This release takes place whenthe coated microparticles of AP are brought into contact with thegastrointestinal juices.

The uncoated microparticles of AP (i.e. before coating) can be e.g.:

inert cores covered with at least one layer containing AP;

or microparticles of pure AP;

or granules formed of a matrix of supporting excipients, including theAP.

In the case of supported granules, the inert core or support can becomposed of sucrose and/or saccharose and/or dextrose and/or lactoseand/or a sucrose/starch mixture. The inert core or support can also be acellulose microsphere or any other particle of pharmaceuticallyacceptable excipient. Particles of xanthan gum, guar gum, calciumphosphate or calcium carbonate may be mentioned as non-limiting examplesof inert supports. Their mean diameter can be between 10 and 200microns, between 20 and 150 microns or between 50 and 100 microns.

These coated microparticles of the “reservoir” type (or individuallycoated microparticles) can be likened to vehicles for the transport andrelease of at least one AP in the small intestine or even the largeintestine.

Examples which may be mentioned of coated microparticles for modifiedrelease of the AP are those described in the following patent documents:EP-B-0 709 087 and WO-A-03/030878.

Coating on the Microparticles of AP

Advantageously, the coated microparticles of AP comprise at least onecoating layer (Ra), preferably only one coating layer (Ra), whichassures the modified release of the AP and simultaneously impartscrushing resistance to the coated microparticles of AP so as to avoidmisuse.

Particularly preferably, the coating layer (Ra) is designed in such away that, in the event of crushing, it allows maintenance of anon-immediate (i.e. modified) release for at least some of the coatedmicroparticles for modified release of the AP.

The crushing envisaged here can be e.g. any crushing performed by thetechniques normally employed by misusers, namely, in particular:mortar/pestle, coffee grinder, between two spoons, by crunching/chewing,etc.

In one valuable embodiment, the coating layer (Ra) is designed in such away that, in the event of crushing, it allows maintenance of a modifiedrelease for at least 40%, preferably at least 60% and particularlypreferably at least 80% of the coated microparticles for modifiedrelease of the AP.

Preferably, the anti-crushing coating layer (Ra) comprises:

(A1) at least one film-forming (co)polymer (A1) insoluble in thegastrointestinal juices;

(A2) at least one (co)polymer (A2) soluble in the gastrointestinaljuices;

(A3) at least one plasticizer (A3);

(A4) optionally at least one surfactant and/or lubricant and/or mineraland/or organic filler (A4).

According to a purely illustrative and non-limiting selection of theinvention:

(A1) is selected from the group comprising:

water-insoluble cellulose derivatives, preferably ethyl cellulose and/orcellulose acetate,

acrylic polymers, e.g. copolymers of (meth)acrylic acid and an alkyl(e.g. methyl) ester, copolymers of an acrylic and methacrylic acid estercarrying at least one quaternary ammonium group (preferably at least onecopolymer of an alkyl (meth)acrylate and trimethylammonioethylmethacrylate chloride), and more precisely the products marketed underthe trademark EUDRAGIT® RS and/or RL,

polyvinyl acetates,

and mixtures thereof;

(A2) is selected from the group comprising:

nitrogen-containing (co)polymers, preferably from the group comprisingpoly-acrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) andpoly-N-vinyl-lactams,

water-soluble cellulose derivatives,

polyvinyl alcohols (PVA),

polyalkylene oxides, preferably polyethylene oxides (PEO),

polyethylene glycols (PEG),

and mixtures thereof,

PVP being particularly preferred;

(A3) is selected from the group comprising:

cetyl alcohol esters,

glycerol and its esters, preferably from the following subgroup:acetylated glycerides, glycerol monostearate, glyceryl triacetate andglycerol tributyrate,

phthalates, preferably from the following subgroup: dibutyl phthalate,diethyl phthalate, dimethyl phthalate, dioctyl phthalate,

citrates, preferably from the following subgroup: acetyl tributylcitrate, acetyl triethyl citrate, tributyl citrate, triethyl citrate,

sebacates, preferably from the following subgroup: diethyl sebacate,dibutyl sebacate,

adipates,

azelates,

benzoates,

vegetable oils,

fumarates, preferably diethyl fumarate,

malates, preferably diethyl malate,

oxalates, preferably diethyl oxalate,

succinates, preferably dibutyl succinate,

butyrates,

cetyl alcohol esters,

salicylic acid,

triacetin,

malonates, preferably diethyl malonate,

castor oil (this being particularly preferred),

and mixtures thereof.

(A4) is selected from the group comprising:

anionic surfactants, preferably from the subgroup comprising alkalimetal or alkaline earth metal salts of fatty acids, stearic and/or oleicacid being preferred,

and/or non-ionic surfactants, preferably from the following subgroup:

polyethoxylated oils, preferably polyethoxylated hydrogenated castoroil,

polyoxyethylene/polyoxypropylene copolymers,

polyethoxylated sorbitan esters,

polyethoxylated castor oil derivatives,

stearates, preferably calcium, magnesium, aluminum or zinc stearates,

stearylfumarates, preferably sodium stearylfumarate,

glycerol behenates,

talcum,

colloidal silica,

titanium oxide, magnesium oxide,

bentonite,

microcrystalline cellulose,

kaolin,

aluminum silicate,

and mixtures thereof.

In addition to the qualitative parameters defining the coatedmicroparticles according to the invention, it can be specified that,according to an advantageous quantitative modality, the coating layer(Ra) comprises the following in % by weight, based on the total weightof the coating:

10≦A1≦90, preferably 15≦A1≦80 and particularly preferably 60≦A1≦80;

5≦A2≦50, preferably 10≦A2≦40 and particularly preferably 10≦A2≦25;

1≦A3≦30, preferably 2≦A3≦20 and particularly preferably 5≦A3≦15;

0≦A4≦40, preferably 0≦A4≦30 and particularly preferably 0≦A4≦20,

the sum of the percentages being equal to 100.

Furthermore, the release rate is regulated for example in the followingmanner:

by control of the thickness of the coating (Ra);

by the weight ratios between the components A1, A2, A3 and optionally A4of the coating (Ra).

Advantageously, the coating on the coated microparticles for modifiedrelease of the AP can comprise, in addition to the essentialconstituents A1, A2, A3 and optionally A4, other conventionalingredients known to those skilled in the art, such as, in particular,colorants, pigments, preservatives, flavorings, etc., and mixturesthereof.

Another noteworthy characteristic of the coating (Ra) on the coatedmicroparticles is the fact that the coating layer (Ra) represents afraction by weight Tp, expressed in % by dry weight, based on the totalweight of the coated microparticles, such that: Tp≧15, Tp preferablybeing between 30 and 60, particularly preferably between 40 and 60 andvery particularly preferably between 45 and 55 or about 50.

Without wishing to be bound by theory, this relatively high coating rateenables the coating layer (Ra) to assure the modified release of the APand simultaneously to impart crushing resistance to the coatedmicroparticles of AP so as to avoid misuse.

Without implying a limitation, the preferred coated microparticles of APaccording to the invention are those having a mean diameter less than orequal to 1000 μm, preferably of between 50 and 800 μm, particularlypreferably of between 100 and 600 μm and very particularly preferably ofbetween 100 and 300 μm.

Unless indicated otherwise, the diameters of microparticles referred toin the present disclosure are mean diameters by volume.

As regards the preparation of the coated microparticles, the techniquesthat are advantageously used for depositing the coating for modifiedrelease of the AP, or depositing the active layer based on the AP, aretechniques known to those skilled in the art, for example the techniqueof spray coating in a fluidized air bed, wet granulation, compaction orextrusion/spheronization.

Outer Coating

In one particular variant of the invention, the coated microparticlesfor modified release of the AP have an outer coating designed in such away that, in the manufacture of tablets, it contributes to maintaining amodified release for at least some of said coated microparticles of APfor modified release of the AP. The outer coating is composed of atleast one deformable organic constituent with a melting point of between40° C. and 120° C., preferably of between 45° C. and 100° C.

In one preferred variant, the outer coating comprises at least 10% byweight of deformable organic constituent.

In particular, in one variant of the invention, the deformable organicconstituent included in the outer coating is selected from polyalkyleneglycols, particular preference being given to polyethylene glycols witha molecular weight of 6,000 to 20,000 D.

In another variant, the deformable organic constituent of the outercoating is a fat or mixture of fats selected e.g. from the group of fatscomprising hydrogenated vegetable oils, fatty acids, fatty alcohols,fatty acid and/or fatty alcohol esters, polyolefins, and mineral,vegetable, animal or synthetic waxes, particular preference being givento fatty acid esters such as diglycerides and triglycerides and mixturesthereof, glycerol behenate and hydrogenated castor, soya, cottonseed andpalm oils.

In one additional variant, the outer coating comprises:

a mineral filler, for example silica or titanium dioxide, or an organicfiller, for example microcrystalline cellulose,

and/or at least one lubricant, for example magnesium stearate or sodiumbenzoate,

and/or at least one hydrophilic polymer such as water-soluble cellulosederivatives, synthetic polymers, preferably polyvinylpyrrolidone,acrylic and methacrylic polymers or polyvinyl alcohols (PVA),

and/or at least one surfactant.

Preferably, the outer coating represents from 5 to 50%, preferably from10 to 30% and particularly preferably in the order of 20% by dry weight,based on the total weight of the overcoated microparticles of AP.

The expression “overcoated microparticle” denotes a coated microparticleof AP that also comprises an outer coating as defined above, i.e. anouter coating which, in the manufacture of tablets, contributes tomaintaining a modified release for at least some of said coatedmicroparticles of AP for modified release of the AP.

Additional information on the outer coating can be found in publishedpatent application WO-A-03/077888.

Viscosifier (Vb)

Preferably, the viscosifier (Vb) is selected from those which aresoluble in at least one of the following solvents: water, alcohols,ketones and mixtures thereof, said viscosifier(s) being capable ofincreasing the viscosity of the extraction liquid so as to thwartmisuse, especially by injection.

“Water” is understood as meaning any aqueous solvent such as waterstricto sensu or any aqueous solution, for example of an organic acid(e.g. acetic acid), saline solutions, sodas or drinks. “Alcohols” areunderstood as meaning any alcohols taken on their own or in a mixturewith one another. “Ketones” are understood as meaning any ketones takenon their own or in a mixture with one another.

Particularly preferably, the viscosifier (Vb) is selected from thefollowing groups of polymers:

polyacrylic acids and derivatives thereof, and/or

polyalkylene glycols (e.g. polyethylene glycol), and/or

polyalkylene oxides (e.g. polyethylene oxides), and/or

polyvinylpyrrolidones, and/or

gelatins, and/or

polysaccharides, preferably from the subgroup comprising sodiumalginate, pectins, guars, xanthans, carrageenans, gellans and cellulosederivatives (e.g. hydroxypropyl methyl cellulose, methyl cellulose,hydroxyethyl cellulose, carboxymethyl cellulose),

and mixtures thereof.

According to one modality of the invention, the viscosifier Vb is apolyoxyethylene with a high molecular weight, e.g. with a molecularweight of 1 million g/mol to 8 million g/mol, for example of 2 million,5 million or 7 million g/mol.

Preferably, the viscosifier Vb, e.g. the high-molecular polyoxyethylene,is included in microparticles distinct from the microparticles of AP.

Particularly preferably, the microparticles of AP and the microparticlesof viscosifier Vb have a similar size distribution and a similar densityand are inseparable by sieving.

According to one preferred modality, the viscosifier (Vb) is capable ofincreasing the viscosity of the liquid used for possible extraction soas to trap the extracted AP in the viscous medium.

This viscosifier (Vb) makes it possible to increase the viscosity of theextraction liquid e.g. to beyond 100 mPa·s, preferably 200 mPa·s,particularly preferably beyond 500 mPa·s and very particularlypreferably 1000 mPa·s.

It is also to the Applicant's credit to have proposed, in one variant,viscosifiers (Vb) that are effective in the case of both aqueous phaseextraction and organic solvent extraction. Advantageously, theseviscosifiers (Vb) are mixtures of hydrophilic compounds and hydrophobiccompounds so as to ensure that the extraction liquid has a highviscosity (above 100 mPa·s, for example), whether it be aqueous ororganic.

As far as the amount of viscosifier (Vb) is concerned, this can easilybe determined by those skilled in the art. Said amount corresponds tothe minimum amount necessary to bring the viscosity of 2.5 ml ofextraction liquid to a value greater than or equal to 100 mPa·s.

In several variants which can be combined with one another, in thepharmaceutical formulation according to the invention at least oneviscosifier (Vb) is present:

in and/or on microparticles,

and/or in an outer coating on all or some of the microparticles of AP,

and/or in the free state, i.e. neither contained in nor supported bymicroparticles.

Advantageously, at least part of the viscosifier is in the form ofmicro-particles that are inseparable from the coated or uncoatedmicroparticles of AP.

Excipients in the Free State

The pharmaceutical formulation can optionally contain one or morepharmaceutically acceptable excipients in the free state, i.e. neithercontained in nor supported by microparticles of AP, said excipientcontributing to the crushing resistance of the coated microparticles ofAP.

Preferably, these excipients contributing to the crushing resistance ofthe coated microparticles of AP are selected from the group comprising:

calcium stearate;

glycerol palmitostearate;

magnesium oxide;

polyalkylene glycols, e.g. polyethylene glycols;

polyvinyl alcohol;

sodium benzoate;

stearic acid;

maize starch;

talcum;

colloidal silica;

zinc stearate, magnesium stearate;

stearylfumarate;

and mixtures thereof.

In alternative embodiments of the invention, at least part of theviscosifier is:

in the free state, i.e. neither contained in nor supported by coated oruncoated microparticles of AP (alternative 1), or

in the form of microparticles that are distinct from the coated oruncoated microparticles of AP (alternative 2).

Advantageously, in alternative 2, the microparticles of viscosifier areinseparable from the coated or uncoated microparticles of AP. In termsof the present disclosure, the expression “inseparable” means e.g.inseparable by conventional means such as sieving or centrifugation.

In alternative 2, the viscosifier is e.g.:

in and/or on microparticles,

and/or in an outer coating on all or some of the microparticles of AP.

Still in alternative 2, the microparticles comprising the viscosifierare preferably physically indiscernible from the microparticles of AP sothat they cannot easily be sorted by any appropriate physical means. Themicroparticles comprising the viscosifier are indiscernible from themicroparticles of AP especially by having the same size and/or samedensity and/or same shape and/or same color.

In another alternative, the viscosifier is e.g.:

in and/or on microparticles,

and/or in an outer coating on all or some of the microparticles of AP.

In one preferred embodiment, the pharmaceutical formulation according tothe invention is multimicroparticulate. If this pharmaceuticalformulation comprises microparticles of AP (e.g. aAP) and microparticlesof viscosifier (Vb), said microparticles preferably have a similar sizedistribution and a similar density and are preferably inseparable bysieving. Thus the microparticles of viscosifier cannot be separated fromthe coated or uncoated microparticles of AP.

In another preferred embodiment, the pharmaceutical formulationaccording to the invention is multimicroparticulate. If thispharmaceutical formulation comprises microparticles of AP (e.g. aAP) andmicroparticles of viscosifier (Vb), said microparticles preferably havethe same size distribution and the same density and are preferablyinseparable by sieving. Thus the microparticles of viscosifier cannot beseparated from the coated or uncoated microparticles of AP.

Sequestering Agent Q

Obviously, in the case where the microparticulate pharmaceuticalformulation comprises at least one salt of at least one analgesic activeprinciple, those skilled in the art may add at least one sequesteringagent to said pharmaceutical formulation so as to form a poorly solublecomplex with the AP in solution in an aqueous or aqueous-alcoholicdrink.

The sequestering agent is e.g. a salt whose ion of opposite polarity tothat of the AP is preferably an organic ion. Thus, for a cationic activeprinciple, this sequestering agent is e.g. an organic salt like sodiumdocusate, or an anionic polymer. The sequestering agent can also be e.g.a salt of an ion exchange resin.

In terms of the present invention, a sequestering agent Q is present inthe pharmaceutical formulation in a free form, i.e. non-complexed.“Non-complexed” means that no complex or chemical interaction existsbetween the sequestering agent Q and the salt of the active principle,AP, in the solid pharmaceutical form.

If the AP salt and the sequestering agent Q are present simultaneouslyin a solvent, e.g. in the case of an illicit attempt to extract the AP,the sequestering agent Q is capable of inducing complexation or achemical interaction with the AP salt in said solvent. In terms of thepresent invention, the sequestering agent Q is considered to be “capableof inducing complexation” with the AP salt if the sequestering agent Qis capable of inducing complexation of the AP salt in at least onecustomary solvent selected from water and aqueous solutions such aswater/ethanol mixtures, alcohol, alcoholic drinks, sodas, vinegar,hydrogen peroxide and mixtures thereof. Advantageously, the sequesteringagent Q is capable of inducing complexation of the AP salt in more thanone of these customary solvents.

The sequestering agents Q used to trap the AP, especially analgesic AP,are inoffensive, even when used regularly. These products are inert fromthe pharmacological point of view and are approved by the variouspharmacopeias and drug registration authorities.

In one pharmaceutical formulation according to the invention, at leastone sequestering agent Q is present:

in microparticles devoid of AP, and/or

on microparticles, and/or

in the free state, i.e. neither contained in nor supported bymicroparticles.

Preferably, in one pharmaceutical formulation according to theinvention, the sequestering agent Q is present in a first phase separatefrom at least one second phase, said second phase containing at leastone AP salt. For example, the pharmaceutical formulation comprisesmicroparticles of AP salt and microparticles of sequestering agent Qthat are distinct. Advantageously, said microparticles have a similarsize distribution the a similar density and are inseparable by sieving.

Preferably, the sequestering agent Q comprises a salt containing ionscapable of forming a complex with the AP in solution. These ions arepreferably organic ions of opposite polarity to that of the AP insolution: if the AP is in anionic form in solution, the sequesteringagent Q comprises an organic cation, a metal cation or a mixturethereof. Likewise, if the AP is in cationic form in solution, thesequestering agent Q comprises an organic anion.

For example, the following salts containing an organic anion may bementioned:

anionic organic salts such as sodium dodecylsulfate or sodium docusate;

anionic polymers such as (meth)acrylic copolymers (e.g. Eudragit® S andEudragit® L), crosslinked polyacrylic acids (e.g. Carbopol),carboxymethyl cellulose and derivatives thereof, crosslinkedcarboxymethyl cellulose and derivatives thereof, and otherpolysaccharides (e.g. alginate, xanthan gum or gum arabic), andalginate/(sulfonate) propylene glycol;

monovalent or polyvalent salts such as glucuronates, citrates, acetates,carbonates, gluconates, succinates, phosphates, glycerophosphates,lactates, trisilicates, fumarates, adipates, benzoates, salicylates,tartrates, sulfonamides and acesulfames;

saponified fatty acids such as acetic, succinic, citric, stearic andpalmitic acid salts and self-emulsifying glyceryl monooleates;

polyamino acids, proteins or peptides, such as albumins, caseins,globulins and enzymes;

and mixtures thereof.

In another embodiment, the ion of opposite polarity to that of the AP insolution is an organic metal cation or a mixture thereof. For example,the following salts containing an organic or metal cation may bementioned:

cationic salts, e.g. of the metals Ca, Fe, Mg or Zn, in the form ofacesulfames, acetates, adipates, benzoates, carbonates, chlorides,citrates, fluorides, fumarates, gluconates, glucuronates,glycerophosphates, hydroxides, iodates, iodides, lactates, oxides,phosphates, trisilicates, salicylates, succinates, sulfonamides ortartrates;

organic cationic salts such as quaternary ammonium salts, particularlytrimethyl-tetradecylammonium bromide or benzethonium chloride;

cationic polymers such as chitosan and (meth)acrylic copolymers (e.g.Eudragit® RS, Eudragit® RL or Eudragit® E);

polyamino acids, proteins or peptides;

and mixtures thereof.

The sequestering agent Q can be an ion exchange resin, preferably astrongly acidic cation exchange resin when the AP is cationic, or astrongly basic anion exchange resin when the AP is anionic.Advantageously, such an ion exchange resin is contained in a first phaseseparate from a second phase containing the AP.

In one embodiment of the invention, the ion exchange resin is e.g. aderivative of a styrene/divinylbenzene copolymer.

In one embodiment of the invention, the strongly acidic cation exchangeresin will be e.g. a derivative of a sulfonated styrene/divinylbenzenecopolymer, such as Amberlite® IRP69, Amberlite® IR69F (Rohm and Haas),Amberlite 200, Amberlite 200C (Rohm and Haas) or Dowex 88 (Dow) and thelike.

In one embodiment of the invention, the strongly basic anion exchangeresin will be selected e.g. from derivatives of styrene/divinylbenzenecopolymers carrying quaternary ammonium groups, such as Duolite® AP143(Rohm and Haas), Amberlite IRA958, Amberlite IRP67 (Rohm and Haas) andDOWEX 22 (Dow).

The sequestering agent Q in the form of resin can also be selected fromcrosslinked methacrylic acid/divinylbenzene copolymers or one of theirsalts, such as Amberlite® IRP88, Amberlite® IRP64 (Rohm and Haas) andDOWEX MAC-3 (Dow).

The sequestering agent Q in the form of ion exchange resin can also beselected from phenolic polyamines such as Amberlite® IRP58 (Rohm andHaas), and mixtures thereof.

In one embodiment of the invention, the sequestering agent Q in the formof ion exchange resin is in a first phase separate from at least onesecond phase, said second phase comprising the AP salt. For example, thesequestering agent Q in the form of ion exchange resin is contained inmicroparticles distinct from the microparticles comprising the AP salt.The microparticles of AP and the microparticles of sequestering agent Qin the form of ion exchange resin can be in a form such that they have asimilar size distribution, a similar density and are inseparable bysieving.

In a first preferred mode of carrying out the invention, thesequestering agent Q is selected from:

anionic organic salts such as sodium dodecylsulfate or sodium docusate;

cationic organic salts such as quaternary ammonium salts, particularlytrimethyl-tetradecylammonium bromide or benzethonium chloride;

and strongly acidic cation exchange resins or strongly basic anionexchange resins, depending on the polarity of the AP.

In a second preferred mode of carrying out the invention, thesequestering agent Q is selected from:

the strongly acidic cation exchange resins Amberlite® IRP69, Amberlite®IR69F (Rohm and Haas), Amberlite 200, Amberlite 200C (Rohm and Haas) orDowex 88 (Dow), and mixtures thereof, when the AP is cationic;

and the strongly basic anion exchange resins Duolite® AP143 (Rohm andHaas), Amberlite IRA958, Amberlite IRP67 (Rohm and Haas) and DOWEX 22(Dow), and mixtures thereof, when the AP is anionic.

The amount of agent Q is adapted by those skilled in the art bycalculating the amount of ionic charge required to trap all or part ofthe dose of AP contained in the unit form. The amount of sequesteringagent Q must be able to complex enough AP for the remaining amount offree AP in solution to be insufficient to achieve the desired effect inthe event of illicit use. Preferably, the amount of sequestering agent Qis sufficient to complex all the AP from the unit dose.

In one variant, the pharmaceutical formulation can also be a monolithicform (e.g. tablet).

In one embodiment, the pharmaceutical formulation according to theinvention comprises microparticles of viscosifier V and/ormicroparticles of sequestering agent Q, preferably microparticles ofviscosifier V and microparticles of sequestering agent Q. In thisembodiment, the microparticles of viscosifier V and the microparticlesof sequestering agent Q are distinct from the microparticles of AP.

In another embodiment of the invention, the pharmaceutical formulationcomprises microparticles of AP as well as microparticles of viscosifierV and/or microparticles of sequestering agent Q. Preferably, thepharmaceutical formulation comprises these three types ofmicroparticles, i.e. microparticles of AP, microparticles of viscosifierV and microparticles of sequestering agent Q, in one and the same unitform. Advantageously, these microparticles have a similar sizedistribution and a similar density and are inseparable from one anotherby sieving.

In a first variant, the pharmaceutical formulation according to theinvention cannot be converted to a dry form with immediate release ofthe AP which can be administered by sniffing.

In a second variant, the pharmaceutical formulation according to theinvention cannot be converted to an injectable form with immediaterelease of the AP.

In a third variant, the pharmaceutical formulation according to theinvention comprises modified-release AP and optionally immediate-releaseAP. This variant can be combined with the first and second variantsreferred to above, which means that, in a pharmaceutical formulationcontaining modified-release AP and immediate-release AP, themodified-release AP cannot be converted to a dry form which can beadministered by sniffing or to an immediate-release injectable form.

In a fourth variant, the pharmaceutical formulation according to theinvention is characterized in that extraction of the AP by chewingand/or crushing is not effective.

In a fifth variant, the pharmaceutical formulation according to theinvention is characterized in that it is devoid of AP antagonist(s).

In a sixth variant, the pharmaceutical formulation according to theinvention is characterized in that it comprises at least one APantagonist. With knowledge of the AP used, those skilled in the art caneasily determine the appropriate antagonist(s).

Of course, any combination of at least two of these six variants isincluded in the present invention (except combination of the fifth andsixth variants).

Active Principle(s)

The AP used belongs e.g. to at least one of the following families ofactive substances: amphetamines, analgesics, anorexigenics, antalgics,antidepressants, antiepileptics, antimigraine substances,antiparkinsonism substances, antitussives, anxiolytics, barbiturates,benzodiazepines, hypnotics, laxatives, neuroleptics, opiates,psychostimulants, psychotropic substances, sedatives and stimulants. Inthe case where the AP is an analgesic AP (aAP), it is preferably anopioid.

Even more precisely, the AP used is selected from the followingcompounds: anileridine, acetorphine, acetyl-alpha-methylfentanyl,acetyldihydro-codeine, acetylmethadol, alfentanil, allylprodine,alpha-cetylmethadol, alpha-meprodine, alpha-prodine, alpha-methadol,alpha-methylfentanyl, alpha-methylthiofentanyl, atropine, butorphanol,benzethidine, benzylmorphine, beta-hydroxyfentanyl,beta-hydroxymethyl-3-fentanyl, beta-cetylmethadol, beta-meprodine,beta-methadol, beta-prodine, bezitramide, buprenorphine, dioxaphenylbutyrate, clonitazene, cyclazocine, cannabis, cetobemidone, codeine,coca, cocaine, codoxime, dezocine, dimenoxadol, dipipanone,desomorphine, dextromoramide, dextropropoxyphene, diampromide,diethylthiambutene, difenoxin, dihydrocodeine, dihydroetorphine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,diphenoxylate, drotebanol, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene, ecgonine, ephedrine,etorphine, etoxeridine, fentanyl, furethidine, heroin, hydrocodone,hydromorphinol, hydromorphone, hydroxypethidine, isomethadone,ketobemidone, levallorphan, lofentanil, levomethorphan, levomoramide,levophenacylmorphan, levorphanol, meptazinol, meperidine, metazocine,methadone, methyldesorphine, methyl dihydromorphine, methylphenidate,methyl-3-thiofentanyl, methyl-3-fentanyl, metopon, moramide,morpheridine, morphine, myrophine, nalbuphine, narceine, nicomorphine,norlevorphanol, normethadone, nalorphine, normorphine, nicocodine,nicodicodine, nicomorphine, noracymethadol, norcodeine, norpipanone,opium, oxycodone, oxymorphone, papavereturn, phenadoxone, phenoperidine,promedol, properidine, propiram, propoxyphene, parafluorofentanyl,pentazocine, pethidine, phenampromide, phenazocine, phenomorphan,pholcodine, piminodine, piritramide, proheptazine, propanolol,racemethorphan, racemoramide, racemorphan, remifentanil, sufentanil,thebacon, thebaine, thiofentanyl, tilidine, trimeperidine, tramadol,their pharmacologically acceptable salts, esters, hydrates, polymorphsand isomers, and mixtures thereof.

The pharmaceutical formulation according to the invention can compriseat least one analgesic active principle (aAP) and at least oneadditional AP that is different from the aAP. This non-analgesic AP ispreferably selected from the group comprising antidepressants,amphetamines, anorexics, non-analgesic painkillers, antiepileptics,antimigraine substances, antiparkinsonism substances, antitussives,anxiolytics, barbiturates, benzodiazepines, hypnotics, laxatives,neuroleptics, psychostimulants, psychotropic substances, sedatives,stimulants, anti-inflammatories, their pharmacologically acceptablesalts, esters, hydrates, polymorphs and isomers, and mixtures thereof.

The following may be mentioned among the anti-inflammatory activeprinciples that can be envisaged: ibuprofen, acetaminophen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, amineoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam, theirpharmacologically acceptable salts, esters, hydrates, polymorphs andisomers, and mixtures thereof.

Even more precisely, the analgesic AP used is selected from the groupcomprising oxycodone hydrochloride, morphine sulfate, oxymorphonehydro-chloride, hydromorphone hydrochloride, hydrocodone hydrochlorideand tramadol hydrochloride.

In terms of the invention, the expression “pharmaceutical formulation”is understood in the broad sense, i.e. veterinary or dieteticformulations, in particular, are encompassed.

According to another of its features, the invention relates to aformulation which is characterized in that it comprises a plurality ofmicroparticles (coated or uncoated microparticles of AP; optionallymicroparticles of viscosifier) as defined above, e.g. at least 500,preferably from 1,000 to 1,000,000 and particularly preferably from5,000 to 500,000 microparticles.

According to another of its features, the invention relates to apharmaceutical formulation comprising a plurality of populations ofcoated microparticles of AP, said populations being distinguished fromone another by their release kinetics and/or the AP they contain.

Without implying a limitation, it must nevertheless be emphasized thatthe pharmaceutical formulation according to the invention is ofparticular value in that it can take the form of a single daily oraldose comprising from 500 to 500,000 microparticles, including the coatedmicroparticles of AP.

Advantageously, the pharmaceutical formulation comprising coatedmicro-particles according to the invention is in a galenical formselected from the group comprising tablets (advantageously dispersiblein the mouth or stomach), powders, suspensions, syrups, reconstitutablesuspension powders, and capsules.

It may be interesting to mix, in one and the same capsule, one and thesame tablet or one and the same powder, at least two types of coatedmicroparticles of AP whose release kinetics are different but within theframework characteristic of the invention.

The invention further relates to the use of the coated microparticlesdescribed above for the manufacture of novel pharmaceuticalformulations, particularly (but without implying a limitation) for thetherapeutic treatment of pain.

The invention further relates to a method of therapeutic treatment whichis characterized in that it consists in administering the pharmaceuticalformulation as defined above to the patient.

The invention further relates to a method of therapeutic treatment whichis characterized in that it consists in ingesting the pharmaceuticalformulation as defined above according to a given dosage.

The invention further relates to a method for the therapeutic treatmentof pain which is characterized in that it consists in administering thepharmaceutical formulation as defined above to the patient.

The invention further relates to a method for the therapeutic treatmentof pain which is characterized in that it consists in ingesting thepharmaceutical formulation as defined above according to a given dosage,the AP used comprising at least one painkiller, e.g. an analgesic.

The invention further relates to a method of combating the misuse of APwhich is characterized in that it consists essentially in using apharmaceutical formulation as defined above.

The invention further relates to a method of combating the misuse of APwhich is characterized in that it consists essentially in using, in apharmaceutical form, coated microparticles of AP for modified release ofthe AP, said microparticles having a coating layer (Ra) which assuresthe modified release of the AP and simultaneously imparts crushingresistance to the coated microparticles of AP so as to avoid misuse, andoptionally at least one viscosifier (Vb) capable of preventingextraction of the AP contained in the coated microparticles of AP so asto avoid misuse.

Advantageously, the coating layer (Ra) and the viscosifier (Vb), ifpresent, are as defined above.

The invention will be explained more clearly by means of the Examplesbelow, given solely by way of illustration, which afford a clearunderstanding of the invention and demonstrate its different embodimentsand/or modes of implementation, as well as its different advantages.

DESCRIPTION OF THE FIGURES

FIG. 1 shows the dissolution profile in an in vitro reference test (%dissolution D as a function of time T) on the microparticles of Example1: -▪-.

FIG. 2 shows the dissolution profile in an in vitro reference test (%dissolution D as a function of time T) on the microparticles of Example1: -▪-, and Example 2: (a) ---□---, (b) ---◯---, (c) ------, (d)---▴---.

FIG. 3 shows photographs of the contents of a capsule according toExample 3, observed with the naked eye (A) and under an opticalmicroscope (B).

FIG. 4 shows the release profile (% by weight of aAP as a function oftime in hours) of microcapsules in 0.1 N HCl (Example 8).

FIG. 5 shows photographs of the contents of a capsule according toExample 9, observed with the naked eye (A) and under an opticalmicroscope (B).

FIG. 6 shows the release profile of crushed microparticles (blanktriangle) or intact microparticles (ailled square) of Example 9.

EXAMPLES

The reference dissolution test in the Examples which follow is an invitro dissolution test performed as indicated in the EuropeanPharmacopoeia 5th edition, entitled “Dissolution test for solid oralforms”: type II dissolutest performed under SINK conditions, maintainedat 37° C. and stirred at 75 rpm in 900 ml of 0.1 N HCl medium.

Example 1 Microparticles of Oxycodone HCl According to the Invention

A mixture of 1600 g of oxycodone HCl, 100 g of Klucel® EF(hydroxy-propyl cellulose/Aqualon) and 12,052 g of water is film-coatedonto 300 g of inert cellulose beads (Asahi-Kasei) in a GPCG1 fluidizedair bed (Glatt®). 450 g of the resulting granules are then coated with amixture composed of 315 g of ethyl cellulose (Ethocel 20 Premium/DOW),81 g of povidone (Plasdone PVP K29/32/ISP), 36 g of castor oil, 18 g ofCremophor RH 40 (macrogolglyceroli hydroxystearas/BASF) and 12,020 g ofethanol.

The coating represents 50% of the weight of the microparticle andassures that the active principle is released over about 4 h, as shownin FIG. 1. The release profile is determined under the conditions of thereference dissolution test.

Example 2 Crushing of the Microparticles of Oxycodone HCl PreparedAccording to Example 1

200 mg of microparticles prepared in Example 1 (i.e. a dose of 80 mg ofoxycodone HCl) are crushed by different methods representing differentpossible ways of misuse:

(a) by crushing vigorously for 2 minutes (˜120 rotations) with a pestleand mortar (250 ml),

(b) by pressing 8 times between two spoons,

(c) by using an “LGS pulverizer” tablet mill (LGS Health Products, USA),

(d) by using a coffee grinder for 30 seconds.

The release profiles of the crushed microparticles are shown in FIG. 2.The release profile is determined under the conditions of the referencedissolution test.

The release profiles of Example 1 (intact microparticles) and Example 2(crushed microparticles) are similar in terms of the test for the f2similarity factor (f2>50), calculated as indicated by the FDA (Guidancefor Industry SUPAC-MR: Modified release solid oral dosage forms, p. 32).

Thus crushing has little or even no effect on the release of theoxycodone from the microparticles.

Example 3 Appearance of the Contents of a Capsule According to theInvention

200 mg of microparticles prepared in Example 1 (i.e. a dose of 80 mg ofoxycodone HCl) are mixed with the following viscosifiers: 90 mg ofKlucel HF (hydroxypropyl cellulose/Aqualon), 20 mg of PolyOx WSR 303Sentry (poly-ethylene oxide/Dow) and 20 mg of Xantural 180(xanthan/cpKelco) previously sieved to between 100 and 600 μm. The wholeis incorporated into a size 0 gelatin capsule.

FIG. 3 shows photographs of the contents of the capsule, observed withthe naked eye (A) and under an optical microscope (B).

As shown in FIG. 3(A), observed with the naked eye, the microparticlesof active principle and the microparticles of viscosifiers are:

indistinguishable,

inseparable by sieving.

In the photograph of FIG. 3(B) obtained by optical microscopy (notescale), there are only two distinct populations of particles: on the onehand spherical microparticles of oxycodone HCl and microparticles of twoviscosifiers, and on the other hand rod-shaped particles of a 3rdviscosifier. Given the very small size of these particles (about 0.2mm), they cannot be separated from one another.

Example 4 Test for Syringe Extraction of a Form According to theInvention

200 mg of microparticles prepared in Example 1 (i.e. a dose of 80 mg ofoxycodone HCl) are mixed with 90 mg of Klucel HF (hydroxypropylcellulose/Aqualon), 20 mg of PolyOx WSR 303 Sentry (polyethyleneoxide/Dow) and 20 mg of Xantural 180 (xanthan/cpKelco) previously sievedto between 100 and 600 μm. The whole is incorporated into a size 0gelatin capsule.

The capsule is opened and the contents are crushed according to Example2(a) with a mortar and pestle and then mixed for 10 min with 2.5 ml ofextraction liquid at ambient temperature or at the boil. The solution isthen taken up with a 2.5 ml syringe (with an 18G needle) through cottonwool serving as a filter. The amount of oxycodone HCl extracted isanalyzed by HPLC or UV and is shown in Table 1.

The low extraction yields observed (<20%) are totally dissuasive forpotential misusers.

Example 5 Test for Syringe Extraction of a Form According to theInvention

200 mg of microparticles prepared in Example 1 (i.e. a dose of 80 mg ofoxycodone HCl) are mixed with 150 mg of Klucel HXF (hydroxypropylcellulose/Aqualon), 50 mg of PolyOx WSR 303 Sentry (polyethyleneoxide/Dow) and 30 mg of Carbopol 971P (carbomer/BF Goodrich). Themixture is incorporated into a size 00 gelatin capsule.

The capsule is opened and the contents are crushed according to Example2(a) with a mortar and pestle and then mixed for 10 min with 10 ml ofextraction liquid at ambient temperature or at the boil. The solution isthen taken up with a 10 ml syringe (with an 18G needle) through cottonwool serving as a filter. The amount of oxycodone HCl extracted isanalyzed by HPLC or UV and is shown in Table 2.

The low extraction yields observed (<20%) are totally dissuasive forpotential misusers.

Example 6 Test for Syringe Extraction of a Form According to theInvention

150 g of Klucel HXF (hydroxypropyl cellulose/Aqualon), 50 g of PolyOxWSR 303 Sentry (polyethylene oxide/Dow), 30 g of Carbopol 971P(carbomer/BF Goodrich) and 10 g of povidone (Plasdone PVP K29/32/ISP)are wet-granulated on a MiPro apparatus. The granules are passed througha 100-600 μm sieve.

250 mg of the resulting granules are added to 200 mg of microparticlesprepared in Example 1 (i.e. a dose of 80 mg of oxycodone HCl). The wholeis incorporated into a size 0 gelatin capsule. The capsule is opened andthe contents are crushed according to Example 2(a) with a mortar andpestle and then mixed for 10 min with 10 ml of extraction liquid atambient temperature or at the boil. The solution is then taken up with a10 ml syringe (with an 18G needle) through cotton wool serving as afilter. The amount of oxycodone HCl extracted is analyzed by HPLC or UVand is shown in Table 3.

The low extraction yields observed (<20%) are totally dissuasive forpotential misusers.

Example 7 Manufacture of a Tablet According to the Invention

200 g of microparticles prepared in Example 1 are mixed with 90 g ofKlucel HF (hydroxypropyl cellulose/Aqualon), 20 g of PolyOx WSR 303Sentry (polyethylene oxide/Dow), 20 g of Xanthural 180(xanthan/cpKelco), 100 g of lactose (Tablettose/Meggle GmbH), 10 g ofmagnesium stearate (Brenntag AG) and 30 g of croscarmellose sodium(Ac-Di-Sol/FMC Bipolymer).

470 mg tablets (i.e. a dose of oxycodone of 80 mg) are manufacturedusing a Korsch reciprocating press.

The tablet obtained is crushed according to Example 2(a) with a mortarand pestle and then mixed for 10 min with 2.5 ml of extraction liquid atambient temperature or at the boil. The solution is then taken up with a2.5 ml syringe (with an 18G needle) through cotton wool serving as afilter. The amount of oxycodone HCl extracted is analyzed by HPLC or UVand is shown in Table 4.

The low extraction yields observed (<20%) are totally dissuasive forpotential misusers.

Example 8 Microparticles of Oxycodone HCl According to the Invention

Step 1: Granules

1615 g of oxycodone and 85 g of povidone (Plasdone® K29-32/ISP) aredispersed in a mixture containing 2052 g of water and 1105 g of ethanol.The solution is sprayed onto 300 g of cellulose spheres (Asahi-Kasei) ina Glatt GPCG1 fluidized air bed.

Step 2: Anti-Crushing Microparticles

315 g of ethyl cellulose (Ethocel 20 Premium/Dow), 81 g of povidone(Plasdone K29-32/ISP), 18 g of macrogolglyceroli hydroxystearas(Cremophor RH40/BASF) and 36 g of castor oil (Garbit huilerie) aresolubilized in a mixture composed of 3105 g of acetone and 2070 g ofisopropanol. This solution is sprayed onto 450 g of granules (preparedin step 1).

The coating represents 50% of the weight of the microparticle andassures that the is released as shown in FIG. 4. The release profile isdetermined under the conditions of the reference dissolution test.

Example 9 Contents of a Capsule According to the Invention

230 mg of microparticles obtained in step 2 of Example 8, 100 mg ofcrushed and sieved Amberlite IR69F (sodium polystyrenesulfonate), 70 mgof sieved Polyox WSR 303 Sentry (polyethylene oxide), 3.8 mg ofmagnesium stearate and 1.9 mg of Aerosil 200 (colloidal silica) areintroduced into a size 0 gelatin capsule.

As shown in FIG. 5, observed with the naked eye (A) and under an opticalmicroscope (B), the microparticles of active principle and themicroparticles of viscosifiers are:

indistinguishable,

inseparable by sieving.

Example 10 Crushing of the Contents of a Capsule Prepared According toExample 9

The contents of the capsule prepared in Example 9 are crushed for 2minutes in a mortar and pestle.

The release profiles of the crushed microparticles are shown in FIG. 6.The release profile is determined under the conditions of the referencedissolution test.

The release profiles of the intact and crushed products are similar.Thus crushing has little or even no effect on the release of theoxycodone from the microparticles.

Example 11 Test for Syringe Extraction of the Contents of a CapsulePrepared According to Example 9

A capsule prepared according to Example 9 is opened and the contents arecrushed for 2 minutes with a mortar and pestle and then mixed for 10 minwith 2.5 ml of extraction liquid at ambient temperature (A) or at theboil (B). The solution is then taken up with a 2.5 ml syringe (witheither an 18G needle or a 27G needle) through cotton wool serving as afilter. The amount of oxycodone HCl extracted is analyzed by HPLC or UVand is shown in Tables 5 and 6.

The low extraction yields observed (<20%) are totally dissuasive forpotential misusers.

Example 12 Test for Extraction of the Contents of a Capsule According toExample 9 into Drinks

A capsule prepared according to Example 9 is opened and the contents arecrushed for 2 minutes with a mortar and pestle and then mixed with 100ml of non-alcoholic drink or 50 ml of alcoholic drink as indicated inthe Table below:

Solvent Volume (ml) Tap water 100 Tap water with 2 g/l of NaCl 100 pH1.2 (HCl) with 2 g/l of NaCl 100 Sprite ® 100 Pepsi-Cola ® 100 SmirnoffTwisted Apple (5% alcohol) 100 Absolut ® vodka (40% alcohol) 50

The solution is then taken up and the amount of oxycodone HCl extractedis analyzed by HPLC or UV and is shown in Table 7.

The low extraction yields observed, even for long extraction times, aretotally dissuasive for potential misusers.

TABLE 1 (Example 4) % oxycodone HCl extracted with the 18 G syringeLiquid at ambient Liquid at temperature the boil Tap water 0.2 1Water/ethanol (60/40 v/v) 3 8 Ethanol 18 1

TABLE 2 (Example 5) % oxycodone HCl extracted with the 18 G syringeLiquid at ambient Liquid at temperature the boil Tap water 1 2Water/ethanol (60/40 v/v) 4 7 Ethanol 19 8

TABLE 3 (Example 6) % oxycodone HCl extracted with the 18 G syringeLiquid at ambient Liquid at temperature the boil Tap water 1 2Water/ethanol (60/40 v/v) 5 8 Ethanol 19 9

TABLE 4 (Example 7) % oxycodone HCl extracted with the 18 G syringeLiquid at ambient Liquid at temperature the boil Tap water 0.5 2Water/ethanol (60/40 v/v) 4 10 Ethanol 19 2

TABLE 5 Amount of AP extracted (%) using a 2.5 ml syringe equipped witha 27 G needle (Example 11) % oxycodone HCl extracted with the 27 Gsyringe Liquid at ambient Liquid at temperature the boil Tap water 0 1Water/ethanol (60/40 v/v) 0 4 Absolute ethanol 14 0

TABLE 6 Amount of AP extracted (%) using a 2.5 ml syringe equipped withan 18 G needle (Example 11) % oxycodone HCl extracted with the 18 Gsyringe Liquid at ambient Liquid at temperature the boil Tap water 0 1Water/ethanol (60/40 v/v) 3 8 Absolute ethanol 18 1

TABLE 7 Amount of AP extracted (%) from different drinks as a functionof time (Example 12) extraction time Solvent 1 h 21 h Tap water 8 <45Tap water with 2 g/l of NaCl 8 <45 pH 1.2 (HCl) with 2 g/l of NaCl 14<45 Sprite ® 3 <45 Pepsi-Cola ® 3 <45 Smirnoff Twisted Apple (5%alcohol) 23 <45 Absolut ® vodka (40% alcohol) 24 <45

1-56. (canceled)
 57. A method of combating the misuse of activeprinciple (AP) comprised in a solid oral pharmaceutical formulation,whereby at least part of the AP is contained in coated microparticles ofAP for modified release of the AP, whereby said microparticles have acoating layer (Ra) that provides modified release of the AP andsimultaneously provides resistance to crushing to the coatedmicroparticles of AP, whereby said at least one coating layer (Ra)comprises: at least one film-forming (co)polymer (A1) insoluble in thegastrointestinal juices; at least one (co)polymer soluble in thegastrointestinal juices (A2); and at least one plasticizer (A3).
 58. Themethod of claim 57, whereby said at least one coating layer (Ra)comprises the following (in % by weight, based on the total weight ofthe coating): 10≦A1≦90, 5≦A2≦50, and 1≦A3≦30.
 59. The method of claim57, whereby said at least one film-forming (co)polymer (A1) is selectedfrom the group consisting of: water-insoluble cellulose derivatives,ethyl cellulose, cellulose acetate, acrylic polymers, copolymers of(meth)acrylic acid alkyl ester, copolymers of acrylic and methacrylicacid esters carrying at least one quaternary ammonium group, copolymersof alkyl(meth)acrylate and trimethylammonioethyl methacrylate chloride),polyvinyl acetates, and mixtures thereof; whereby said at least one(co)polymer soluble in the gastrointestinal juices (A2) is selected fromthe group consisting of: nitrogen-containing (co)polymers,polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP),poly-N-vinyllactams, water-soluble cellulose derivatives, polyvinylalcohols (PVA), polyalkylene oxides, polyethylene oxides (PEO),polyethylene glycols (PEG), and mixtures thereof; whereby said at leastone plasticizer (A3) is selected from the group consisting of: cetylalcohol esters, glycerol, glycerol esters, acetylated glycerides,glycerol monostearate, glyceryl triacetate, glycerol tributyrate,phthalates, dibutyl phthalate, diethyl phthalate, dimethyl phthalate,dioctyl phthalate, citrates, acetyl tributyl citrate, acetyl triethylcitrate, tributyl citrate, triethyl citrate, sebacates, diethylsebacate, dibutyl sebacate, adipates, azelates, benzoates, vegetableoils, fumarates, diethyl fumarate, malates, diethyl malate, oxalates,diethyl oxalate, succinates, dibutyl succinate, butyrates, cetyl alcoholesters, salicylic acid, triacetin, malonates, diethyl malonate, castoroil, and mixtures thereof.
 60. The method of claim 58, whereby said atleast one coating layer (Ra) further comprises at least one surfactant,lubricant, mineral or organic filler (A4) in the following amount (in %by weight, based on the total weight of the coating): 0≦A4≦40.
 61. Themethod of claim 60, whereby said at least one surfactant, lubricant,mineral or organic filler (A4) is selected from the group consisting of:anionic surfactants, alkali metal, alkaline earth metal salts of fattyacids, stearic acid, oleic acid, non-ionic surfactants, polyethoxylatedoils, polyethoxylated hydrogenated castor oil,polyoxyethylene/polyoxypropylene copolymers, polyethoxylated sorbitanesters, polyethoxylated castor oil—based compound, stearates, calciumstearate, magnesium stearate, aluminum stearate, zinc stearates,stearylfumarates, sodium stearylfumarate, glycerol behenates, talcum,colloidal silica, titanium oxide, magnesium oxide, bentonite,microcrystalline cellulose, kaolin, aluminum silicate, and mixturesthereof.
 62. The method of claim 57, whereby said at least one coatinglayer (Ra) represents a fraction by weight (Tp)>15% by dry weight, basedon the total weight of the coated microparticles.
 63. The method ofclaim 57, whereby said coated microparticles have a mean diameter lessthan or equal to 1000 μm.
 64. The method of claim 57, whereby saidformulation is in the form of a tablet, and whereby said coatedmicroparticles comprise at least one outer coating composed of at leastone deformable organic constituent with a melting point of between 40°C. and 120° C.
 65. The method of claim 64, whereby said at least oneouter coating represents from 5 to 50% of the total weight of the saidcoated microparticles of AP by dry weight.
 66. The method of claim 57,whereby said formulation comprises at least one viscosifier (Vb). 67.The method of claim 66, whereby said at least one viscosifier (Vb) issoluble in at least one of the following solvents: water, alcohols,ketones and mixtures thereof.
 68. The method of claim 67, whereby saidat least one viscosifier (Vb) is selected from the group consisting of:polyacrylic acids, polyacrylic acids derivatives, polyalkylene glycols,polyethylene glycol, polyalkylene oxides, polyethylene oxides,polyvinylpyrrolidones, gelatins, polysaccharides, sodium alginate,pectins, guars, xanthans, carrageenans, gellans, cellulose derivatives,hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethylcellulose, carboxymethyl cellulose, and mixtures thereof.
 69. The methodof claim 67, whereby said at least one viscosifier (Vb) is apolyoxyethylene with an average molecular weight of 1 million g/mol to 8million g/mol.
 70. The method of claim 66, whereby at least part of saidviscosifier (Vb) is in the form of microparticles that are distinct fromthe microparticles comprising the AP, and inseparable by sieving fromthe microparticles of AP.
 71. The method of claim 66, whereby saidformulation further comprises at least one AP sequestering agent Q,whereby a complex with the AP is formed in solution.
 72. The method ofclaim 71, whereby said at least one AP sequestering agent Q consists ofa salt containing at least one ion that forms a complex with theextracted AP salt in solution.
 73. The method of claim 72, whereby saidat least one ion is an organic ion with opposite polarity to that of theAP in solution.
 74. The method of claim 72, whereby said at least one APsequestering agent Q comprises a salt selected from the group consistingof: anionic organic salts, carboxymethyl cellulose, carboxymethylcellulose derivatives, crosslinked carboxymethyl cellulose, crosslinkedcarboxymethyl cellulose derivatives, polysaccharides, phosphates,trisilicates, saponified fatty acids, self-emulsifying glycerylmonooleates, polyamino acids, proteins, peptides, cationic metallicsalts, cationic organic salts, cationic polymers, and mixtures thereof.75. The method of claim 72, whereby said at least one AP sequesteringagent Q is a salt that is either a strongly acidic cation exchange resinwhen the AP is cationic, or a strongly basic anion exchange resin whenthe AP is anionic.
 76. The method of claim 75, wherein said at least oneAP sequestering agent Q comprises a styrene/divinylbenzene copolymer.77. The method Of claim 75, wherein said at least one AP sequesteringagent Q comprises a sulfonated styrene/divinylbenzene copolymer.
 78. Themethod of claim 75, wherein said at least one AP sequestering agent Qcomprises a styrene/divinylbenzene copolymer carrying quaternaryammonium groups.
 79. The method of claim 75, wherein said at least oneAP sequestering agent Q comprises a crosslinked methacrylicacid/divinylbenzene copolymer or one of its salts.
 80. The method ofclaim 75, wherein said exchange resin comprises a phenolic polyamine.81. The method of claim 70, whereby at least part of said viscosifier(Vb) is in the form of microparticles that are distinct from themicroparticles comprising the AP, whereby said at least one APsequestering agent Q is in the form of microparticles that are distinctfrom the microparticles comprising the AP and whereby saidmicroparticles of Vb and said microparticles of Q are inseparable bysieving from the microparticles of AP.
 82. The method of claim 70,whereby said formulation further comprises at least one excipient in afree state.
 83. The method of claim 82, whereby said at least oneexcipient is selected from the group consisting of: calcium stearate,glycerol palmitostearate, magnesium oxide, polyalkylene glycols,polyethylene glycols, polyvinyl alcohol, sodium benzoate, stearic acid,maize starch, talcum, colloidal silica, zinc stearate, magnesiumstearate, stearylfumarate, and mixtures thereof.
 84. The method of claim57, whereby said formulation further comprises immediate release AP. 85.The method of claim 57, whereby said at least one AP is selected fromthe group consisting of: amphetamines, narcotics, anorexigenics,antidepressants, antiepileptics, antiparkinsonism substances,anxiolytics, barbiturates, benzodiazepines, hypnotics, neuroleptics,opioids, psychostimulants, psychotropic substances and mixtures thereof.86. The method of claim 57, whereby said at least one AP is selectedfrom the group consisting of: anileridine, acetorphine,acetyl-alpha-methylfentanyl, acetyldihydrocodeine, acetylmethadol,alfentanil, allylprodine, alpha-cetylmethadol, alpha-meprodine,alpha-prodine, alpha-methadol, alpha-methylfentanyl,alpha-methylthiofentanyl, atropine, butorphanol, benzethidine,benzylmorphine, beta-hydroxyfentanyl, beta-hydroxymethyl-3-fentanyl,beta-cetylmethadol, beta-meprodine, beta-methadol, beta-prodine,bezitramide, buprenorphine, dioxaphenyl butyrate, clonitazene,cyclazocine, cannabis, cetobemidone, codeine, coca, cocaine, codoxime,dezocine, dimenoxadol, dipipanone, desomorphine, dextromoramide,dextropropoxyphene, diampromide, diethylthiambutene, difenoxin,dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, diphenoxylate, drotebanol,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene, ecgonine, ephedrine, etorphine, etoxeridine, fentanyl,furethidine, heroin, hydro-codone, hydromorphinol, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levallorphan, lofentanil,levomethorphan, levomoramide, levophenacylmorphan, levorphanol,meptazinol, meperidine, metazocine, methadone, methyldesorphine,methyldihydromorphine, methylphenidate, methyl-3-thiofentanyl,methyl-3-fentanyl, metopon, moramide, morpheridine, morphine, myrophine,nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone,nalorphine, normorphine, nicocodine, nicodicodine, nicomorphine,noracymethadol, norcodeine, norpipanone, opium, oxycodone, oxymorphone,papavereturn, phenadoxone, phenoperidine, promedol, properidine,propiram, propoxyphene, parafluorofentanyl, pentazocine, pethidine,phenampromide, phenazocine, phenomorphan, pholcodine, piminodine,piritramide, proheptazine, propanolol, racemethorphan, racemoramide,racemorphan, remifentanil, sufentanil, thebacon, thebaine, thiofentanyl,tilidine, trimeperidine, tramadol, their pharmacologically acceptablesalts, esters, hydrates, polymorphs and isomers, and mixtures thereof.87. The method of claim 57, whereby said at least one AP is selectedfrom the group consisting of: oxycodone hydrochloride, morphine sulfate,oxymorphone hydrochloride, hydromorphone hydrochloride, hydrocodonehydrochloride, tramadol hydrochloride, and mixtures thereof.
 88. Themethod of claim 57, whereby said formulation does not contain an APantagonist.
 89. The method of claim 57, whereby said formulationcomprises at least two different populations of coated microparticles ofAP, whereby each population of coated microparticles has differentrelease kinetics.